Neurotrophic factors are traditionally viewed as secretory proteins that regulate long-term neuronal survival and differentiation, but recent studies show that they also play an important role in synapse development and plasticity. My lab was among the first to demonstrate this novel function of trophic factors. We have made two important discoveries. One is that brain-derived neurotrophic factor (BDNF) acutely potentiates high frequency synaptic transmission, and promotes hippocampal LTP, a cellular model for learning and memory. The other is that neurotrophin-3 (NT3) facilitates the long-term maturation at developing neuromuscular junction (NMJ). We are continuing the studies on neurotrophic regulation of synapses, focusing on three areas: 1) the mechanisms by which BDNF regulates long-term potentiation (LTP). Last year, we showed that BDNF facilitates LTP by enhancing synaptic response to tetanus and promoting synaptic vesicle docking in the presynaptic terminals at the CA synapses of the hippocampus. Using a conditional knockout mouse line in which the BDNF receptor TrkB has been selectively deleted in postsynaptic neurons, we demonstrated this year that at CA1 hippocampal synapses, BDNF acts exclusively on presynaptic neurons but not on postsynaptic neurons, an issue under considerable debate (J. Neurosci.). 2) signal transduction mechanisms for acute effects of neurotrophins. We showed last year that in the hippocampus, BDNF modulation of synaptic plasticity is mediated by signaling pathways involving MAP kinase and Phosphoinositide-3 kinase (PI3K), but not Phospholipase C-gamma. This year, we demonstrated that acute modulation of NT3 on transmitter release at the NMJ uses an unusual mechanism which involves calcium release from intracellular stores through inositol 1, 4, 5-trisphosphate (IP3) and/or ryanodine receptors, leading to an activation of calcium/calmodulin kinase II (CaMKII) (J. Cell Biol.). Further, we demonstrated using photo-uncaging that simultaneous activation of PI3K and IP3 receptors is not only necessary but also sufficient to mediate the effect of NT3 (Nature Neurosci., revision). 3) Activity-dependent modulation of neurotrophin receptors. To understand how synapse specific neurotrophic regulation is achieved, we initiated this year a line of research on the role of neuronal/synaptic activity in the trafficking of the neurotrophin receptors TrkB. We revealed an activity-dependent modulation of the insertion of TrkB into the plasma membrane of cultured hippocampal neurons. This effect requires Ca2+ influx through NMDA-type glutamate receptors and Ca2+ channels, and involves CaMKII (J. Cell Biol.). These findings may not only provide insights into the mechanistic link between activity-dependent and neurotrophic modulation of synaptic efficacy, but also have general implications in the cell biology of growth factor signaling.